Metastasis of cells from a primary tumor in mammals leads to the spread of cancer to other tissues of the body (1-3). The spread of metastases may occur via the blood or the lymphatics or through both routes. Cancer cell metastasis commonly occur in lungs, liver, brain, and the bones. These secondary aggressive cancers lead to organ dysfunction and ultimately death (Metastatic Cancer: Questions and Answers”. National Cancer Institute). To date, there are few effective treatments for metastatic cancers.
Signaling pathways that promote cell detachment and/or metastasis are largely unknown. However, we have discovered signaling pathways that unexpectedly regulate cell adhesion to the extra-cellular matrix (ECM) are prime candidates for promoting metastasis (4). These pathways may be impacted upon by the many genetic and epigenetic changes as a cell transitions to malignancy, together with microenvironmental changes such as changes in hormone signaling.
Wound dehiscence is the premature “bursting” open of a wound along surgical suture. It is a surgical complication that results from poor wound healing. Risk factors are age, diabetes, obesity, poor knotting/grabbing of stitches and trauma to the wound after surgery. Agents that promote cell adhesion could speed healing. Retinal detachment is a disorder of the eye in which the retina peels away from its underlying layer of support tissue. Initial detachment may be localized, but without rapid treatment the entire retina may detach, leading to vision loss and blindness. Agents that promote cell adhesion could speed healing. Aortic dissection is a tear in the wall of the aorta that causes blood to flow between the layers of the wall of the aorta and force the layers apart. Aortic dissection is a medical emergency and can quickly lead to death, even with optimal treatment. If the dissection tears the aorta completely open (through all three layers), massive and rapid blood loss occurs. Agents that promote cell adhesion could speed healing. Major skin trauma (e.g. burns, amputation) can be treated with temporary, artificial or autologous skin replacement. Agents that promote cell adhesion could speed healing. Blastocyst attachment to the endometrium of the uterine wall is essential for pregnancy and is a cause of infertility. Agents that promote blastocyst attachment could prevent infertility. Tissue engineering is a technique that allows for the generation of biological substitutes that restore, maintain, or improve tissue function or a whole organ. This technology includes the use of stem cells grown in the presence of scaffolds and growth factors for the generation of new tissues for transplantation into recipients. Examples of this technology include but are not limited to the development of bioartificial windpipes for implantation into recipients, cartilage for repair of knee, skin for the repair of wounds, and other bioartificial organs for the repair of blood vessels, bladders, pancreas, foreskin, penis, bone, liver, and heart. Agents that promote stem cell attachment could speed the generation and function of these tissues for transplantation, as well as promote their attachment and integration into the organ or body that they are transplanted into. Agents that promote stem cell attachment also would enhance 3-D printing of stem cells for the creation of tissues. Edible artificial animal muscle tissue can be cultured in vitro as a meat source. Agents that enhance muscle and fat cell attachment to collagen or other matrices, or allow solid meat formation, would speed the production and improve the texture of in vitro meat. Psoriasis, eczema and dandruff are skin conditions that result in the shedding of skin cells and inflammation. Agents that prevent skin detachment and inflammation would prevent psoriasis, eczema and dandruff. Unfortunately, signaling pathways that regulate cell adhesion are largely unknown.
We have identified a pathway, the activin receptor type II (ActRII) signaling pathway, that regulates cell adhesion. Blocking ActRII signaling alters cellular morphology and increases cell detachment. Cell detachment correlates with an increase in the expression of ADAM-15, a disintegrin which cleaves integrin molecules (5) and cadherin (6). In this context, it has recently been demonstrated that the expression of ADAM-15 is strongly correlated with the metastatic potential of prostate, breast (7) and pancreatic cancers (8) and is highly up-regulated in aggressive prostate cancer (6). Furthermore, ADAM-15 has been shown to be involved in cell migration and invasion (9, 10). Signal transduction components of the activin signaling pathway are highly down-regulated in prostate cancer (11, 12). In vitro, inhibition of ADAM15 expression in PC-3 cells decreases cell migration and adhesion to specific extracellular matrix proteins, and is accompanied by a reduction in the cleavage of N-cadherin by ADAM15 at the cell surface (6). In patients with bone metastasis from prostate cancer, circulating levels of activin A are significantly higher (13). These findings indicate that ActRII mediates cell adhesion (and viability) via the regulation of ADAM-15 expression and function.
Modulation of ActRII signaling and associated disintegrins can be used to identify drugs that enhance ActRII signaling and promote cell attachment, or inhibit the expression and/or function of disintegrins associated with promoting cell detachment. Accordingly, it is desirable to provide a method, kit, and apparatus for utilizing ActRII signaling and associated disintegrins to identify compounds and conditions capable of modulating adhesion characteristics of cell.